以chitin/PLGA顆粒誘發SD大鼠缺血性腦中風之初步研究

The preliminary study of ischemic stroke induced by chitin/PLGA particles in Sprague-Dawley rats

張博勛(Po-Hsun Chang)

指導教授 ： 蔡義弘

高雄醫學大學/藥學院/藥學研究所/碩士(2012年)

摘要

腦中風(Stroke)，近年來已攀升為全球十大死亡原因的第三位，僅次於缺血性心臟病及惡性腫瘤，而在台灣亦呈現相同的趨勢。根據腦中風發生之原因，可將其分做缺血性(Ischemic)及出血性(Hemorrhagic)腦中風，其中又以缺血性腦中風最為常見。
本實驗室於過去研究中，曾將Chitin 與PLGA 相互結合來製成微粒，並利用其在含水環境下可迅速膨脹的特性，來做為中大腦動脈栓塞術中的誘發栓塞物質，而建立出與臨床病理機轉相似的栓塞型缺血性腦中風動物模型，且可於動物清醒下誘發腦中風。
本篇研究，將延續使用過去研究所建立之動物模型，並針對危險因子及實驗大鼠品系對於腦中風動物模型之影響加以探討。同時，亦將加入生物指標之概念做為其中一項監測項目。簡單地說，本篇首先將藉由Streptozotocin 來誘發SD大鼠產生第一型糖尿病，並與健康SD大鼠進行腦中風後之預後比較，此外，也將選用SD及Wistar兩種實驗室常用之大鼠品系進行腦中風後之預後比較。
初步結果顯示，藉由調整緩衝區長度可建立出間隙型(lacunar)及瀰漫型(Diffuse)腦中風，兩種不同型態但再現性良好之腦中風結果。其中，健康大鼠之小間隙型腦中風動物模型在各項腦中風的評估結果上，其預後皆明顯優於瀰漫型腦中風動物模型，且兩品系之健康大鼠皆有相似結果。不過，糖尿病之影響，除了明顯惡化腦中風的預後結果外，同時也大大提升實驗大鼠的死亡率，及小間隙型腦中風動物模型之再現性。最後，本篇亦藉由染色技術發現血腦障壁在腦中風後的第二小時即遭受破壞，並於第四小時起有腦部損傷之情形發生，同時，所呈現出的結果皆可與臨床治療之目標及重要性得以相互印證。

關鍵字

缺血性腦中風 ； 中大腦動脈栓塞術 ； Chitin/PLGA 顆粒 ； 大鼠品系 ； 危險因子

並列摘要

Stroke is the third leading cause of morbidity and mortality in the Western world and same in Taiwan, following ischemic heart disease and cancer. It occurs when a blood vessel in the brain either becomes blocked or bursts.
In our previous study, we manufactured artificial embolic particles by blending chitin and PLGA to induce middle cerebral artery occlusion in rat which is a kind of animal model of embolic ischemic stroke, especially in conscious.
In this study, we wanted to know the influence of strains and risk factors to the stroke animal model, and we also added the concept of biomarker as one of monitors. Briefly, we used streptozotocin to induce acute type I diabetes in SD rats at first. Then, we selected chitin/PLGA blending microparticles at the range of 53 to 63 μm which can expand almost 40% as artificial emboli to induce ischemic stroke. Finally, we compared the differences between the SD rat with or without acute type I diabetes by cerebral blood flow, blood sugar, amino acid, volume of brain damage and functional behavior analysis.
After a series of experiments, we established two kinds of ischemic stroke animal models, lacunar and diffuse type, in both health rat by controlling different lengths of buffer area when inducing stroke, and the strains of rats had no significant impact on the results. Also, lacunar type ischemic stroke animal models had the better outcome after stroke than diffuse type. Nevertheless, diabetes leaded the more serious outcome after stroke than health rat, including the higher mortality and less reproduction of lacunar type ischemic stroke animal models. Besides, we also found the dsyfunction of brain-blood barrier and infarction of brain happened at the two and four hours afer stroke, respectively, and could also prove the purpose and importance in clinical treatment.

並列關鍵字

Ischemic stroke ； Middle cerebral artery occlusion (MCAO) ； Chitin/PLGA particles ； Strains ； Risk factors

參考文獻

1. Cooper R, Cutler J, Desvigne-Nickens P, Fortmann SP, Friedman L, Havlik R, Hogelin G, Marler J, McGovern P, Morosco G, Mosca L, Pearson T, Stamler J, Stryer D, Thom T. Trends and disparities in coronary heart disease, stroke, and other cardiovascular diseases in the united states: Findings of the national conference on cardiovascular disease prevention. Circulation. 2000;102:3137-3147

2. Elkins JS, Johnston SC. Thirty-year projections for deaths from ischemic stroke in the united states. Stroke. 2003;34:2109-2112

3. Joseph T. DiPiro RLT, Gary C. Yee, Gary R. Matzke, Barbara G. Wells, L. Michael Posey. Pharmacotherapy 8th edition 2011

4. Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, Ford E, Furie K, Go A, Greenlund K, Haase N, Hailpern S, Ho M, Howard V, Kissela B, Kittner S, Lackland D, Lisabeth L, Marelli A, McDermott M, Meigs J, Mozaffarian D, Nichol G, O'Donnell C, Roger V, Rosamond W, Sacco R, Sorlie P, Stafford R, Steinberger J, Thom T, Wasserthiel-Smoller S, Wong N, Wylie-Rosett J, Hong Y. Heart disease and stroke statistics--2009 update: A report from the american heart association statistics committee and stroke statistics subcommittee. Circulation. 2009;119:480-486

5. David Gamon ADB. Building mental muscle 2nd edition.